Cell
Volume 184, Issue 10, 13 May 2021, Pages 2696-2714.e25
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Article
Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

https://doi.org/10.1016/j.cell.2021.03.048Get rights and content
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Highlights

  • Blockage of CMA in neurons leads to proteotoxicity and neuronal dysfunction

  • CMA regulates a specific neuronal subproteome at risk of aggregation

  • CMA loss and disease-driven proteotoxicity are synergistic on proteome collapse

  • Chemical enhancement of CMA ameliorates proteotoxicity-driven neurodegeneration

Summary

Components of the proteostasis network malfunction in aging, and reduced protein quality control in neurons has been proposed to promote neurodegeneration. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective autophagy shown to degrade neurodegeneration-related proteins, in neuronal proteostasis. Using mouse models with systemic and neuronal-specific CMA blockage, we demonstrate that loss of neuronal CMA leads to altered neuronal function, selective changes in the neuronal metastable proteome, and proteotoxicity, all reminiscent of brain aging. Imposing CMA loss on a mouse model of Alzheimer’s disease (AD) has synergistic negative effects on the proteome at risk of aggregation, thus increasing neuronal disease vulnerability and accelerating disease progression. Conversely, chemical enhancement of CMA ameliorates pathology in two different AD experimental mouse models. We conclude that functional CMA is essential for neuronal proteostasis through the maintenance of a subset of the proteome with a higher risk of misfolding than the general proteome.

Keywords

aging
Alzheimer’s disease
chemical activators of autophagy
chaperones
lysosomes
neurodegeneration
protein aggregation
proteotoxicity
supersaturated proteome
tau

Cited by (0)

12

Lead contact

13

Present address: Institut des Maladies Neurodégénératives, CNRS, Université de Bordeaux, France

14

Present address: Neurobiology Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain

15

Present address: Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark